Thienopyridyl compounds that inhibit vanilloid receptor subtype 1 (VR1) and uses thereof

ABSTRACT

The present invention discloses fused thienopyridyl compounds of general formula (I) 
                         
wherein X 1 -X 6 , R 5 -R 7 , Z 1  and L are as defined in the description. The resent invention also discloses a method for inhibiting the VR1 receptor in mammals using these compounds, a method for controlling pain, urinary incontinence, bladder overactivity, and inflammatory thermal hyperalgesia in mammals, and pharmaceutical compositions including those compounds.

CROSS REFERENCE SECTION TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 11/293,012filed on Dec. 2, 2005, which claims priority to U.S. ProvisionalApplication Ser. No. 60/633,957 filed on Dec. 7, 2004, and are allincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to compounds of formula (I), which areuseful for treating disorders caused by or exacerbated by vanilloidreceptor activity, pharmaceutical compositions containing compounds offormula (I) and are useful in treating pain, bladder overactivity, andurinary incontinence.

BACKGROUND OF INVENTION

Nociceptors are primary sensory afferent (C and M fibers) neurons thatare activated by a wide variety of noxious stimuli including chemical,mechanical, thermal, and proton (pH<6) modalities. The lipophillicvanilloid, capsaicin, activates primary sensory fibers via a specificcell surface capsaicin receptor, cloned as VR1. The intradermaladministration of capsaicin is characterized by an initial burning orhot sensation followed by a prolonged period of analgesia. The analgesiccomponent of VR1 receptor activation is thought to be mediated by acapsaicin-induced desensitization of the primary sensory afferentterminal. Thus, the long lasting anti-nociceptive effect of capsaicinhas prompted the clinical use of capsaicin analogs as analgesic agents.Further, capsazepine, a capsaicin receptor antagonist can reduceinflammation-induced hyperalgesia in animal models. VR1 receptors arealso localized on sensory afferents, which innervate the bladder.Capsaicin or resiniferatoxin has been shown to ameliorate incontinencesymptoms upon injection into the bladder.

The VR1 receptor has been called a “polymodal detector” of noxiousstimuli since it can be activated in several ways. The receptor channelis activated by capsaicin and other vanilloids and thus is classified asa ligand-gated ion channel. VR1 receptor activation by capsaicin can beblocked by the competitive VR1 receptor antagonist, capsazepine. Thechannel can also be activated by protons. Under mildly acidic conditions(pH 6-7), the affinity of capsaicin for the receptor is increased,whereas at pH<6, direct activation of the channel occurs. In addition,when membrane temperature reaches 43° C., the channel is opened. Thusheat can directly gate the channel in the absence of ligand. Thecapsaicin analog, capsazepine, which is a competitive antagonist ofcapsaicin, blocks activation of the channel in response to capsaicin,acid, or heat.

The channel is a nonspecific cation conductor. Both extracellular sodiumand calcium enter through the channel pore, resulting in cell membranedepolarization. This depolarization increases neuronal excitability,leading to action potential firing and transmission of a noxious nerveimpulse to the spinal cord. In addition, depolarization of theperipheral terminal can lead to release of inflammatory peptides suchas, but not limited to, substance P and CGRP, leading to enhancedperipheral sensitization of tissue.

Recently, two groups have reported the generation of a “knock-out” mouselacking the VR1 receptor. Electrophysiological studies of sensoryneurons (dorsal root ganglia) from these animals revealed a markedabsence of responses evoked by noxious stimuli including capsaicin,heat, and reduced pH. These animals did not display any overt signs ofbehavioral impairment and showed no differences in responses to acutenon-noxious thermal and mechanical stimulation relative to wild-typemice. The VR1 (−/−) mice also did not show reduced sensitivity to nerveinjury-induced mechanical or thermal nociception. However, the VR1knock-out mice were insensitive to the noxious effects of intradermalcapsaicin, exposure to intense heat (50-55° C.), and failed to developthermal hyperalgesia following the intradermal administration ofcarrageenan.

The compounds of the present invention are novel VR1 antagonists andhave utility in treating pain, bladder overactivity, urinaryincontinence and inflammatory thermal hyperalgesia.

SUMMARY OF THE PRESENT INVENTION

The present invention discloses fused thienopyridyl compounds, a methodfor inhibiting the VR1 receptor in mammals using these compounds, amethod for controlling pain in mammals, and pharmaceutical compositionsincluding those compounds. More particularly, the present invention isdirected to compounds of formula (I)

-   -   or a pharmaceutically acceptable salt or prodrug thereof,        wherein

- - - is absent or a covalent bond;

X₁ is selected from N and CR₁;

X₂ is selected from N and CR₂;

X₃ is selected from N, NR₃ and CR₃;

X₄ is absent or selected from N and CR₄;

X₅ is selected from N and CH₂;

provided that at least one of X₁, X₂, X₃ and X₄ is N;

X₆ is selected from O, NH and S;

Z₁ is selected from O, NH and S;

Z₂ is absent or selected from NH and O;

L is selected from aryl, alkenylene, alkylene, alkynylene,cycloalkylene, heterocycle, —(CH₂)_(m)O(CH₂)_(n)—, —N(H)O—, and —NHNH—wherein the left end of —(CH₂)_(m)O(CH₂)_(n)— and —N(H)O— is attached toZ₂ and the right end is attached to R₇;

provided that when Z₂ is NH or O then L is other than —N(H)O— or —NHNH—;

m and n are each independently 1-6;

R₁, R₃ and R₅ are each independently selected from hydrogen, alkenyl,alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio,alkynyl, amines, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl,cycloalkylalkyl, ethylenedioxy, formyl, formylalkyl, haloalkoxy,haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl,methylenedioxy, mercapto, mercaptoalkyl, nitro, (CF₃)₂(HO)C—,R_(B)S(O)₂R_(A)N—,

R_(A)OS(O)₂—, R_(B)—S(O)₂—, Z_(A)Z_(B)N—, (Z_(A)Z_(B)N)alkyl,(Z_(A)Z_(B)N)carbonyl, (Z_(A)Z_(B)N)alkylcarbonyl and(Z_(A)Z_(B)N)sulfonyl, wherein Z_(A) and Z_(B) are each independentlyselected from hydrogen, alkyl, alkylcarbonyl, formyl, aryl andarylalkyl;

R₂ and R₄ are each independently selected from the group consisting ofhydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylthio, alkynyl, amines, carboxy, carboxyalkyl,cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, ethylenedioxy, formyl,formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy,hydroxyalkyl, methylenedioxy, mercapto, mercaptoalkyl, nitro,(CF₃)₂(HO)C—, R_(B)S(O)₂R_(A)N—, R_(A)OS(O)₂—, R_(B)—S(O)₂—,Z_(A)Z_(B)N—, (Z_(A)Z_(B)N)alkyl, (Z_(A)Z_(B)N)carbonyl,(Z_(A)Z_(B)N)alkylcarbonyl, (ZAZ_(B)N)sulfonyl, (Z_(A)Z_(B)N)C(═NH)—,(Z_(A)Z_(B)N)C(═NCN)NH—, and (Z_(A)Z_(B)N)C(═NH)NH—;

R_(A) is selected from hydrogen and alkyl;

R_(A) is selected from hydrogen and alkyl;

R_(B) is selected from alkyl, aryl and arylalkyl;

R₆ is absent or selected from hydrogen and alkyl;

provided that R₆ is absent when X₅ is CH₂ and R₆ is selected fromhydrogen and alkyl when X₅ is N; and

R₇ is selected from hydrogen, aryl and heterocycle.

In another embodiment of the present invention there is disclosed apharmaceutical composition comprising a therapeutically effective amountof a compound of formula (I) or a pharmaceutically acceptable saltthereof.

In a further embodiment of the present invention there is disclosedmethod of treating a disorder wherein the disorder is ameliorated byinhibiting vanilloid receptor subtype 1 (VR1) receptor in a host mammalin need of such treatment comprising administering a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

(1) Embodiments

In the principal embodiment, compounds of formula (I) are disclosed

or a pharmaceutically acceptable salt or prodrug thereof, in which - - -is absent or is a covalent bond; X₁ is selected from N and CR₁; X₂ isselected from N and CR₂; X₃ is selected from N, NR₃ and CR₃; X₄ isabsent or selected from N and CR₄; X₅ is selected from N and CH₂;provided that at least one of X₁, X₂, X₃ and X₄ is N; X₆ is selectedfrom O, NH and S; Z₁ is selected from O, NH and S; Z₂ is absent orselected from NH and O; L is selected from aryl, alkenylene, alkylene,alkynylene, cycloalkylene, heterocycle, —(CH₂)_(m)O(CH₂)_(n)—, —N(H)O—,and —NHNH— wherein the left end of —(CH₂)_(m)O(CH₂)_(n)— and —N(H)O— isattached to Z₂ and the right end is attached to R₇; provided that whenZ₂ is NH or O then L is other than —N(H)O— or —NHNH—; m and n are eachindependently 1-6; R₁, R₃ and R₅ are each independently selected fromhydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylthio, alkynyl, amines, carboxy, carboxyalkyl,cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, ethylenedioxy, formyl,formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy,hydroxyalkyl, methylenedioxy, mercapto, mercaptoalkyl, nitro,(CF₃)₂(HO)C—, R_(B)S(O)₂R_(A)N—,R_(A)OS(O)₂—, R_(B)—S(O)₂—, Z_(A)Z_(B)N—, (Z_(A)Z_(B)N)alkyl,(Z_(A)Z_(B)N)carbonyl, (Z_(A)Z_(B)N)alkylcarbonyl and(Z_(A)Z_(B)N)sulfonyl, wherein Z_(A) and Z_(B) are each independentlyselected from hydrogen, alkyl, alkylcarbonyl, formyl, aryl andarylalkyl;R₂ and R₄ are each independently selected from the group consisting ofhydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylthio, alkynyl, amines, carboxy, carboxyalkyl,cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, ethylenedioxy, formyl,formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy,hydroxyalkyl, methylenedioxy, mercapto, mercaptoalkyl, nitro,(CF₃)₂(HO)C—, R_(B)S(O)₂R_(A)N—, R_(A)OS(O)₂—, R_(B)—S(O)₂—,Z_(A)Z_(B)N—, (Z_(A)Z_(B)N)alkyl, (Z_(A)Z_(B)N)carbonyl,(Z_(A)Z_(B)N)alkylcarbonyl, (ZAZ_(B)N)sulfonyl, (Z_(A)Z_(B)N)C(═NH)—,(Z_(A)Z_(B)N)C(═NCN)NH—, and (Z_(A)Z_(B)N)C(═NH)NH—; R_(A) is selectedfrom hydrogen and alkyl; R_(B) is selected from alkyl, aryl andarylalkyl; R₆ is absent or selected from hydrogen and alkyl; providedthat R₆ is absent when X₅ is CH₂ and R₆ is selected from hydrogen andalkyl when X₅ is N; and R₇ is selected from hydrogen, aryl andheterocycle.

In another embodiment, compounds of formula (I) are disclosed, inwhich, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isCR₄; R₁, R₂, R₄, R₅, R₆, R₇, X₅, X₆, Z₁, Z₂, and L are as defined forformula (I) above.

In another embodiment, compounds of formula (I) are disclosed, inwhich, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isCR₄; X₅ is N; X₆ is S; Z₁ is O; Z₂ is NH; L is alkylene; R₁, R₂, R₄, R₅,R₆, and R₇ are as defined in formula (I).

In another embodiment, compounds of formula (I) are disclosed, inwhich, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isCR₄; X₅ is N; X₆ is S; Z₁ is O; Z₂ is NH; L is alkylene; R₅ is ahalogen; and R₁, R₂, R₄, R₆, and R₇ are as defined in formula (I).

In another embodiment, compounds of formula (I) are disclosed, inwhich, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isCR₄; X₅ is N; X₆ is S; Z₁ is O; Z₂ is NH; L is alkylene; R₅ is alkyl;and R₁, R₂, R₄, R₆, and R₇ are as defined for formula (I) above.

In another embodiment, compounds of formula (I) are disclosed, inwhich, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isCR₄; X₅ is N; X₆ is S; Z₁ is O; Z₂ is NH; L is alkylene; R₅ is methyl,R₇ is aryl; and R₁, R₂, R₄ and R₆, are as defined for formula (I) above.

Another embodiment of the present invention comprises compounds offormula (I) in which, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃is N; X₄ is CR₄; X₅ is N; X₆ is S; Z₁ is O; Z₂ is NH; L is alkylene; R₅is methyl, R₇ is phenyl substituted with 0, 1, 2, or 3 substituentsindependently selected from alkoxy, alkyl, alkylsulfonyl, cyano,haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, andZ_(A)Z_(B)N—; and Z_(A), Z_(B); and R₁, R₂, R₄ and R₆ are each hydrogen.

Another embodiment of the present invention comprises compounds offormula (I) in which, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃is N; X₄ is CR₄; X₅ is N; X₆ is S; Z₁ is O; Z₂ is NH; L is alkylene; R₅is methyl, R₇ is naphthyl substituted with 0, 1, 2, or 3 substituentsindependently selected from alkoxy, alkyl, alkylsulfonyl, cyano,haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, andZ_(A)Z_(B)N—; and Z_(A), Z_(B) and R₆ are as defined for formula (I)above.

In another embodiment, compounds of formula (I) are disclosed, inwhich, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isCR₄; X₅ is N; X₆ is S; Z₁ is O; Z₂ is NH; L is aryl; R₇ is heterocycle,and R₁, R₂, R₄, R₅, R₆, are as defined in formula (I).

In another embodiment, compounds of formula (I) are disclosed, inwhich, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isCR₄; X₅ is N; X₆ is S; Z₁ is O; Z₂ is NH; L is indanyl; R₇ isheterocycle, and R₁, R₂, R₄, R₅, R₆, are as defined in formula (I).

In another embodiment, compounds of formula (I) are disclosed, inwhich, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isCR₄; X₅ is N; X₆ is S; Z₁ is O; Z₂ is NH; L is heterocycle; and R₁, R₂,R₄, R₅, R₆, R₇, are as defined for formula (I) above.

In another embodiment, compounds of formula (I) are disclosed, inwhich, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isCR₄; X₅ is N; X₆ is S; Z₁ is O; Z₂ is O; L is alkylene; and R₁, R₂, R₄,R₅, R₆, R₇, are as defined for formula (I) above.

In another embodiment, compounds of formula (I) are disclosed, inwhich, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isCR₄; X₅ is N; X₆ is S; Z₁ is O; Z₂ is O; L is alkylene; R₇ is aryl; andR₁, R₂, R₄, R₅, R₆, are as defined above for formula (I).

In another embodiment, compounds of formula (I) are disclosed, inwhich, - - - is a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isCR₄; X₅ is N; X₆ is S; Z₁ is O; Z₂ is O; L is alkylene; R₇ is phenylsubstituted with 0, 1, 2, or 3 substituents independently selected fromalkoxy, alkyl, alkylsulfonyl, cyano, haloalkoxy, haloalkyl,haloalkylthio, halogen, methylenedioxy, and Z_(A)Z_(B)N—; and Z_(A),Z_(B); and R₁, R₂, R₄, R₅, R₆, are as defined above for formula (I).

In yet another embodiment, compounds of formula (I) are disclosed, inwhich, - - - is a covalent bond; X₁ is CR₁; X₂ is N; X₃ is CR₃; X₄ isCR₄; R₁, R₂, R₄, R₅, R₆, R₇, X₅, X₆, Z₁, Z₂, and L are as defined abovefor formula (I).

The present invention also relates to a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula(I) as defined above or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating a disorderthat is ameliorated by inhibiting vanilloid receptor subtype 1 (VR1)receptor in a host mammal in need of such treatment comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof, where thedisorder is selected from the group consisting of pain, urinaryincontinence, bladder overactivity, and inflammatory thermalhyperalgesia.

Another embodiment of the present invention relates to a method forcontrolling pain in a host mammal in need of such treatment comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to a method oftreating urinary incontinence in a host mammal in need of such treatmentcomprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to a method oftreating bladder overactivity in a host mammal in need of such treatmentcomprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to a method oftreating inflammatory thermal hyperalgesia in a host mammal in need ofsuch treatment comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

(2) Definition of Terms

As used throughout this specification and the appended claims, thefollowing terms have the following meanings:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, methoxymethoxy, ethoxymethoxy and2-ethoxyethoxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl” as used herein, means an alkoxycarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkoxycarbonylalkyl include, but are not limited to,3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and2-tert-butoxycarbonylethyl.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonylalkyl” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkylcarbonylalkyl include, but are not limited to, 2-oxopropyl,3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylene” means a divalent group derived from a straight orbranched chain hydrocarbon of from 1 to 10 carbon atoms. Representativeexamples of alkylene include, but are not limited to, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkylsulfonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkylthio” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, and hexylsulfanyl.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl” as used herein, means a phenyl group, or a bicyclic or atricyclic fused ring system wherein one or more of the fused rings is aphenyl group. Bicyclic fused ring systems are exemplified by a phenylgroup fused to a cycloalkyl group, as defined herein, or another phenylgroup. Tricyclic fused ring systems are exemplified by a bicyclic fusedring system fused to a cycloalkyl group, as defined herein, or anotherphenyl group. Representative examples of aryl include, but are notlimited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl,naphthyl, phenyl and tetrahydronaphthyl.

The aryl groups of this invention can be substituted with 1, 2, 3, 4 or5 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl,alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl,cycloalkyl, cycloalkylalkyl, ethylenedioxy, formyl, formylalkyl,haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl,methylenedioxy, mercapto, mercaptoalkyl, nitro, Z_(A)Z_(B)N—,(Z_(A)Z_(B)N)alkyl, (Z_(A)Z_(B)N)carbonyl, (Z_(A)Z_(B)N)carbonylalkyl,(Z_(A)Z_(B)N)sulfonyl, R_(B)S(O)₂R_(A)N—, R_(A)OS(O)₂— and R_(A)S(O)₂—wherein R_(A) and R_(B) are as defined herein. The aryl groups of thisinvention can be further substituted with any one of an additional aryl,arylalkyl, aryloxy, arylthio, heterocycle, heterocyclealkyl,heterocycleoxy, or heterocyclethio group, as defined herein, wherein theadditional aryl, arylalkyl, aryloxy, arylthio, heterocycle,heterocyclealkyl, heterocycleoxy, and heterocyclethio group can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, carboxy,carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl,ethylenedioxy, formyl, formylalkyl, haloalkoxy, haloalkyl,haloalkylthio, halogen, hydroxy, hydroxyalkyl, methylenedioxy, mercapto,mercaptoalkyl, nitro,

—NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl, (NZ_(A)Z_(B))carbonyl,(NZ_(A)Z_(B))carbonylalkyl, (NZ_(A)Z_(B))sulfonyl, —NR_(A)S(O)₂R_(B),—S(O)₂OR_(A) and —S(O)₂R_(A) wherein R_(A) and R_(B) are as definedherein.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “amino” as used herein, means a NH₂ group.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —CO₂H group.

The term “carboxyalkyl” as used herein, means a carboxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of carboxyalkylinclude, but are not limited to, carboxymethyl, 2-carboxyethyl, and3-carboxypropyl.

The term “cyano” as used herein, means a —CN group.

The term “cyanoalkyl” as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of cyanoalkyl include, butare not limited to, cyanomethyl, 2-cyanoyethyl, and 3-cyanopropyl.

The term “cycloalkyl” as used herein, means a saturated cyclichydrocarbon group containing from 3 to 8 carbons. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cycloalkylalkylinclude, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term “ethylenedioxy” as used herein, means a —O(CH₂)₂O— groupwherein the oxygen atoms of the ethylenedioxy group are attached to theparent molecular moiety through one carbon atom forming a 5 memberedring or the oxygen atoms of the ethylenedioxy group are attached to theparent molecular moiety through two adjacent carbon atoms forming a sixmembered ring.

The term “formyl” as used herein, means a —C(O)H group.

The term “formylalkyl” as used herein, means a formyl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of formylalkyl include, butare not limited to, formylmethyl and 2-formylethyl.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, 2-chloro-3-fluoropentyloxy, and pentafluoroethoxy.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “haloalkylthio” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkylthio group, as defined herein. Representative examples ofhaloalkylthio include, but are not limited to, trifluoromethylthio.

The term “heterocycle” or “heterocyclic” as used herein, means amonocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systemsare exemplified by any 3- or 4-membered ring containing a heteroatomindependently selected from oxygen, nitrogen and sulfur; or a 5-, 6- or7-membered ring containing one, two or three heteroatoms wherein theheteroatoms are independently selected from nitrogen, oxygen and sulfur.The 5-membered ring has from 0-2 double bonds and the 6- and 7-memberedring have from 0-3 double bonds. Representative examples of monocyclicring systems include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl,imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl,isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl,oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl,thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl,thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone),thiopyranyl, triazinyl, triazolyl, and trithianyl. Bicyclic ring systemsare exemplified by any of the above monocyclic ring systems fused to anaryl group as defined herein, a cycloalkyl group as defined herein, oranother monocyclic ring system. Representative examples of bicyclic ringsystems include but are not limited to, for example, benzimidazolyl,benzodioxinyl, benzothiazolyl, benzothienyl, benzotriazolyl,benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, cinnolinyl,indazolyl, indolyl, 2,3-dihydroindolyl, indolizinyl, naphthyridinyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,phthalazinyl, pyranopyridinyl, quinolinyl, quinolizinyl, quinoxalinyl,quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, andthiopyranopyridinyl. Tricyclic rings systems are exemplified by any ofthe above bicyclic ring systems fused to an aryl group as definedherein, a cycloalkyl group as defined herein, or a monocyclic ringsystem. Representative examples of tricyclic ring systems include, butare not limited to, acridinyl, carbazolyl, carbolinyl,dibenzo[b,d]furanyl, dibenzo[b,d]thienyl, naphtho[2,3-b]furan,naphtho[2,3-b]thienyl, phenazinyl, phenothiazinyl, phenoxazinyl,thianthrenyl, thioxanthenyl and xanthenyl.

The heterocycles of this invention can be substituted with 1, 2, or 3substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, arylalkyl,aryloxy, arylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl,cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl,haloalkylthio, halogen, heterocyclealkyl, heterocycleoxy,heterocyclethio, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro,oxo, —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl, (NZ_(A)Z_(B))carbonyl,(NZ_(A)Z_(B))carbonylalkyl, (NZ_(A)Z_(B))sulfonyl, —NR_(A)S(O)₂R_(B),—S(O)₂OR_(A) and —S(O)₂R_(A) wherein R_(A) and R_(B) are as definedherein. The heterocycles of this invention can be further substitutedwith any one of an additional aryl, arylalkyl, aryloxy, arylthio,heterocycle, heterocyclealkyl, heterocycleoxy, or heterocyclethio group,as defined herein, wherein the additional aryl, arylalkyl, aryloxy,arylthio, heterocycle, heterocyclealkyl, heterocycleoxy, andheterocyclethio group can be substituted with 1, 2, or 3 substituentsindependently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy,carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl,ethylenedioxy, formyl, formylalkyl, haloalkoxy, haloalkyl,haloalkylthio, halogen, hydroxy, hydroxyalkyl, methylenedioxy, mercapto,mercaptoalkyl, nitro, —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl,(NZ_(A)Z_(B))carbonyl, (NZ_(A)Z_(B))carbonylalkyl,(NZ_(A)Z_(B))sulfonyl, —NR_(A)S(O)₂R_(B), —S(O)₂OR_(A) and —S(O)₂R_(A)wherein R_(A) and R_(B) are as defined herein.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “mercapto” as used herein, means a —SH group.

The term “mercaptoalkyl” as used herein, means a mercapto group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of mercaptoalkylinclude, but are not limited to, 2-mercaptoethyl and 3-mercaptopropyl.

The term “methylenedioxy” as used herein, means a —OCH₂O— group whereinthe oxygen atoms of the methylenedioxy are attached to the parentmolecular moiety through two adjacent carbon atoms.

The term “nitro” as used herein, means a —NO₂ group.

The term “Z_(A)Z_(B)N—” as used herein, means two groups, Z_(A) andZ_(B), which are appended to the parent molecular moiety through anitrogen atom. Z_(A) and Z_(B) are each independently selected fromhydrogen, alkyl, alkylcarbonyl, formyl, aryl and arylalkyl.Representative examples of Z_(A)Z_(B)N— include, but are not limited to,amino, methylamino, acetylamino, benzylamino, phenylamino, andacetylmethylamino.

The term “(Z_(A)Z_(B)N)alkyl” as used herein, means a Z_(A)Z_(B)N group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of(Z_(A)Z_(B)N)alkyl include, but are not limited to, aminomethyl,2-(methylamino)ethyl, 2-(dimethylamino)ethyl and(ethylmethylamino)methyl.

The term “(Z_(A)Z_(B)N)carbonyl” as used herein, means a Z_(A)Z_(B)Ngroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(Z_(A)Z_(B)N)carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl and(ethylmethylamino)carbonyl.

The term “(Z_(A)Z_(B)N)carbonylalkyl” as used herein, means a(Z_(A)Z_(B)N)carbonyl group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of (Z_(A)Z_(B)N)carbonylalkyl include, but arenot limited to, (aminocarbonyl)methyl, 2-((methylamino)carbonyl)ethyland ((dimethylamino)carbonyl)methyl.

The term “(Z_(A)Z_(B)N)sulfonyl” as used herein, means a Z_(A)Z_(B)Ngroup, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(Z_(A)Z_(B)N)sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl and(ethylmethylamino)sulfonyl.

The term “oxo” as used herein, means ═O.

The term “sulfonyl” as used herein, means a —S(O)₂— group.

(3) Preparation of Compounds of the Present Invention

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic Schemes andExamples, which illustrate a means by which the compounds of the presentinvention can be prepared.

Amines of general formula (8), wherein R₁, R₂, R₄, and R₅ are defined informula (I), may be prepared as described in Scheme 1. Aldehydes ofgeneral formula (1) can be treated with amines of general formula (2) toprovide imines of general formula (3). Imines of general formula (3) canbe treated with a reducing agent such as, but not limited to, 10% Pd/Cunder a hydrogen atmosphere (60 psi) in a solvent such as, but notlimited to, methanol to provide amines of general formula (4). Amines ofgeneral formula (4) can be treated with an sulfonyl or acid chloridesuch as, but not limited to, p-toluenesulfonyl chloride in a solventsuch as, but not limited to, ethyl acetate containing a base such as,but not limited to, triethylamine to provide a protected amine ofgeneral formula (5). Protected amines of general formula (5) can betreated with a concentrated acid such as, but not limited to,hydrochloric acid in a solvent such as, but not limited to, dioxane toprovide cyclized thieno[2,3-c]pyridines of general formula (6).Thieno[2,3-c]pyridines of general formula (6) can be treated with anitrating agent such as, but not limited to, nitric acid in a solvent ofsulfuric acid to provide 3-nitro thieno[2,3-c]pyridines of generalformula (7). 3-Nitro thieno[2,3-c]pyridines of general formula (7) canbe treated with a reducing agent such as, but not limited to,Raney-Nickel in a solvent such as, but not limited to, methanol toprovide 3-amino thieno[2,3-c]pyridines of general formula (8).

Ureas of general formula (12), wherein R₁, R₂, R₄, R₅, R₇, and L are asdefined in formula (I), may be prepared as described in Scheme 2.3-Amino thieno[2,3-c]pyridines of general formula (8), prepared usingstandard chemistry known to those in the art, can be treated withtrichloroacetyl chloride and a base such as, but not limited to,triethylamine in a solvent such as dichloromethane to providetrichloroacetamides of general formula (10). Trichloroacetamides ofgeneral formula (10) can be treated with amines of general formula (9)and a non-nucleophilic base such as, but not limited to, DBU in asolvent such as, but not limited to, acetonitrile to provide ureas ofgeneral formula (12).

Carbamates of general formula (14), wherein R₁, R₂, R₄, R₅, R₇, and Lare as defined in formula (I), may also be prepared as described inScheme 2. Trichloroacetamides of general formula (10) can be treatedwith alcohols of general formula (13) and a non-nucleophilic base suchas, but not limited to, DBU in a solvent such as, but not limited to,acetonitrile to provide carbamates of general formula (14).

Ureas of general formula (4), wherein R₁, R₂, R₄, R₅, R₇, and L are asdefined in formula (I), may be prepared as described in Scheme 3.3-Amino thieno[2,3-c]pyridines of general formula (8) can be treatedwith phosgene or triphosgene and DMAP in a solvent such as, but notlimited to, dichloromethane to provide isocyanates of general formula(15). Isocyanates of general formula (15) can be treated with amines ofgeneral formula (11) in a solvent such as, but not limited to, tolueneor THF or a combination thereof to provide ureas of general formula(12).

Amines of general formula (23), wherein R₁, R₃, R₄, and R₅ are definedin formula (I), may be prepared as described in Scheme 4. Aldehydes ofgeneral formula (16) can be treated with amines of general formula (17)to provide imines of general formula (18). Imines of general formula(18) can be treated with a reducing agent such as, but not limited to,10% Pd/C under a hydrogen atmosphere (60 psi) in a solvent such as, butnot limited to, methanol to provide amines of general formula (19).Amines of general formula (19) can be treated with an sulfonyl or acidchloride such as, but not limited to, p-toluenesulfonyl chloride in asolvent such as, but not limited to, ethyl acetate containing a basesuch as, but not limited to, triethylamine to provide a protected amineof general formula (20). Protected amines of general formula (20) can betreated with a concentrated acid such as, but not limited to,hydrochloric acid in a solvent such as, but not limited to, dioxane toprovide cyclized thieno[3,2-c]pyridines of general formula (21).Thieno[3,2-c]pyridines of general formula (21) can be treated with anitrating agent such as, but not limited to, nitric acid in a solvent ofsulfuric acid to provide 3-nitro thieno[3,2-c]pyridines of generalformula (22). 3-Nitro thieno[3,2-c]pyridines of general formula (22) canbe treated with a reducing agent such as, but not limited to,Raney-Nickel in a solvent such as, but not limited to, methanol toprovide 3-amino thieno[3,2-c]pyridines of general formula (23).

Amines of general formula (32), wherein R₁, R₂, R₄, and R₅ are definedin formula (1), may be prepared as described in Scheme 5. Amines ofgeneral formula (24) can be treated with aldehydes of general formula(25) to provide imines of general formula (26). Imines of generalformula (26) can be treated with alkylating agents such as, but notlimited to, Grignard reagents of general formula (27) in a solvent suchas, but not limited to, THF to provide amines of general formula (28).Amines of general formula (28) can be treated with an sulfonyl or acidchloride such as, but not limited to, p-toluenesulfonyl chloride in asolvent such as, but not limited to, ethyl acetate containing a basesuch as, but not limited to, triethylamine to provide a protected amineof general formula (29). Protected amines of general formula (29) can betreated with a concentrated acid such as, but not limited to,hydrochloric acid in a solvent such as, but not limited to, dioxane toprovide cyclized thieno[2,3-c]pyridines of general formula (30).Thieno[2,3-c]pyridines of general formula (30) can be treated with anitrating agent such as, but not limited to, nitric acid in a solvent ofsulfuric acid to provide 3-nitro thieno[2,3-c]pyridines of generalformula (31). 3-Nitro thieno[2,3-c]pyridines of general formula (31) canbe treated with a reducing agent such as, but not limited to,Raney-Nickel in a solvent such as, but not limited to, methanol toprovide 3-amino thieno[2,3-c]pyridines of general formula (32).

Ureas of general formula (33), wherein R₁, R₃, R₄, R₅, R₇, and L are asdefined in formula (I), and carbamates of general formula (34), whereinR₁, R₃, R₄, R₅, R₇, and L are as defined in formula (I), may be preparedas described in Scheme 6. 3-Amino thieno[2,3-c]pyridine of generalformula (23), prepared using standard chemistry outlined in scheme 4,may be processed as described in Schemes 2-3 to provide ureas of generalformula (33) and carbamates of general formula (34).

Ureas of general formula (35), wherein R₁, R₂, R₄, R₅, R₇, and L are asdefined in formula (I), and carbamates of general formula (36), whereinR₁, R₂, R₄, R₅, R₇, and L are as defined in formula (I), may be preparedas described in Scheme 6. 3-Amino thieno[2,3-c]pyridines of generalformula (32), prepared using standard chemistry outlined in scheme 5,may be processed as described in Schemes 2-3 to provide ureas of generalformula (35) and carbamates of general formula (36).

Amines of general formula (44), wherein R₁, R₂, R₄, and R₅ are definedin formula (I), may be prepared as described in Scheme 7.(3-Nitro-4-pyridyl)acetic esters of general formula (37) can be treatedwith dimethylformamide diethylacetals of general formula (38) in asolvent such as, but not limited to, DMF to provide(3-nitro-4-pyridyl)acetic ester dimethylaminovinyl derivatives ofgeneral formula (39). Dimethylaminovinyl derivatives of general formula(39) can treated with a reducing agent such as, but not limited to, 5%Pd/C under a hydrogen atmosphere (60 psi) in a solvent such as, but notlimited to, ethanol to provide 3-ethoxycarbonyl-6-azaindoles of generalformula (40). 3-Ethoxycarbonyl-6-azaindoles of general formula (40) canbe treated with a base such as, but not limited to, potassium hydroxidein an aqueous solution to provide carboxylic acids of general formula(41). Carboxylic acids of general formula (41) can be thermallydecarboxylated to provide 6-azaindoles of general formula (42).6-Azaindoles of general formula (42) can be treated with a nitratingagent such as, but not limited to, fuming nitric acid to provide3-nitro-6-azaindoles of general formula (43). 3-Nitro-6-azaindoles ofgeneral formula (43) can be treated to a reducing agent such as, but notlimited to, Raney-Nickel in a solvent such as, but not limited to,methanol to provide 3-amino-6-azaindoles of general formula (44).

Ureas of general formula (45), wherein R₁, R₂, R₄, R₅, R₇, and L are asdefined in formula (I), and carbamates of general formula (46), whereinR₁, R₂, R₄, R₅, R₇, and L are as defined in formula (I), may be preparedas described in Scheme 8. 3-Amino-6-azaindoles of general formula (44),prepared using standard chemistry outlined in scheme 7, may be processedas described in Schemes 2-3 to provide ureas of general formula (45) andcarbamates of general formula (46).

(4) Examples

The following Examples are intended as an illustration of and not alimitation upon the scope of the invention as defined in the appendedclaims.

Example 1A (2,2-Dimethoxy-ethyl)-(5-methyl-thiophen-2-ylmethyl)-amine

Added aminoacetaldehyde dimethylacetal (27.5 g, 0.261 mol) to5-methyl-2-thiophenecarboxaldehyde (25.0 g, 0.198 mol) and stirred at 0°C. for 30 min. Heated on rotavap for 30 min to remove excessaminoacetaldehyde. Obtained imine as a dark liquid (42.1 g, 100%).

Dissolved imine (42.1 g, 0.198 mol) in EtOH (170 mL) and added Pd—C(10%, 6.0 g). Reaction was shaken under hydrogen (60 psi) for 40 h.Reaction mixture was filtered and the collected catalyst washed withEtOH. Concentration in vacuo afforded the amine as a red liquid (42.1 g,99%).

MS (ESI+) m/z 216 (M+H)⁺; (ESI−) m/z 214 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.38(s, 3H), 2.68 (d, J 5.4, 1H), 3.25 (s, 6H), 3.79 (s, 2H), 4.64 (t, J5.4, 2H), 6.60 (m, 1H), 6.70 (d, J 3.0, 1H.

Example 1BN-(2,2-Dimethoxy-ethyl)-4-methyl-N-(5-methyl-thiophen-2-ylmethyl)-benzenesulfonamide

Crude (2,2-dimethyoxy-ethyl)-(5-methyl-thiophen-2-ylmethyl)-amine (1)(43.41 g ˜75% pure, 0.15 mol) was dissolved in EtOAc (150 mL) resultingin a yellow solution. Triethylamine (22 mL, 0.16 mol) was added. Themixture was cooled to 0° C. in ice bath. p-Toluenesulfonyl chloride(29.68 g, 0.16 mol) was added in small portions keeping the temperaturebelow 15° C. After addition was complete the mixture was left in icebath and allowed to slowly warm to room temperature and stirred for 20hrs. The milky-yellow mixture was diluted with EtOAc (300 mL) and washedwith water (2×400 mL), 1 M HCl (2×400 mL), water (1×400 mL), sat NaHCO₃(1×400 mL), and brine (1×400 mL), dried (MgSO₄) and condensed to providethe title compound as a reddish-yellow liquid, 50.56 g. Product was notpurified.

Example 1C 2-Methyl-thieno[2,3-c]pyridine

2-Methyl-thieno[2,3-c]pyridine (3): 76059-85:N-(2,2-Dimethoxy-ethyl)-4-methyl-N-(5-methyl-thiophen-2-ylmethyl)-benzenesulfonamide(2) (50.56 g crude) was dissolved in dioxane (250 mL) and conc. HCl (200mL) was added cautiously. The dark red solution was heated at gentlereflux (105 to 110° C.) for 24 hours. The volume was reduced byapproximately half, then diluted with ether (200 mL). The pH wasadjusted to between 7 and 8 using 50% NaOH/H₂O and sat NaHCO₃ solutionwith cooling. More ether (400 mL) was added, the mixture was filtered toremove insoluble material and the phases separated. The organic phasewas washed with water (2×350 mL), dried (MgSO₄) and condensed to darkred-brown oil. Purification was accomplished using Kugelrohrdistillation (120 to 130° C.) to give 11.89 g of title compound as apale yellow liquid.

MS (ESI+) m/z 150 (M+H)⁺; (ESI−) m/z 148 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.64(s, 3H), 7.23 (s, 1H), 7.69 (d, J 6.4, 1H), 8.40 (d, J 6.4, 1H), 9.10(s, 1H); Anal. Calcd for C₈H₇NS.0.9H₂O: C, 58.09; H, 5.36. Found: C,58.01; H, 5.52.

Example 1D 2-Methyl-3-nitro-thieno[2,3-c]pyridine

2-Methyl-thieno[2,3-c]pyridine (5.51 g, 36.9 mmol) was dissolved inconcentrated H₂SO₄ (20 mL) at 0° C. Concentrated HNO₃ (11.6 mL) wasadded dropwise over 15 min, followed by warming to RT. Stirred for 18 hat RT. The solution was poured over ice and adjusted pH to 7 with 50%NaOH/H₂O and sat NaHCO₃ solution. The solution was extracted withportions of CH₂Cl₂ (3×100 mL), dried (MgSO₄) and condensed to yield thetitle compound as a bright yellow solid (3.27 g, 46%).

MS (ESI+) m/z 195 (M+H)⁺; (ESI−) m/z 193 (M−H)⁺; ¹H NMR (CDCl₃) δ 3.02(s, 3H), 8.30 (d, J 5.8, 1H), 8.67 (d, J 5.8, 1H), 9.05 (s, 1H).

Example 1E2,2,2-Trichloro-N-(2-methyl-thieno[2,3-c]pyridin-3-yl)-acetamide

Methyl-3-nitro-thieno[2,3-c]pyridine (2.05 g, 10.6 mmol) was dissolvedin MeOH (250 mL) and added to a suspension of Raney-Nickel (20 g) inMeOH (100 mL). The reaction flask was flushed with H₂. After 3 hours atroom temperature under a balloon of H₂ the reaction mixture was filteredand condensed to provide a yellow solid. This was then dissolved in DCM(100 mL) and triethylamine (1.6 mL, 11.5 mmol) was added. The solutionwas cooled to 0° C. in an ice bath. Trichloroacetyl chloride (1.3 mL,11.6 mmol) was added dropwise. The solution was allowed to slowly warmto room temperature and stirred overnight (16 hrs), then concentrated toa yellow paste and partitioned between equal volumes of water and EtOAc(150 mL each). After separation the organic phase was washed with water(2×70 mL) and brine (1×70 mL), dried (MgSO₄) and condensed to providethe title compound as a tan solid (1.63 g, 42%). Used withoutpurification.

General Coupling Procedure

The product from Example 1A (0.65 g, 2.25 mmol), DBU (0.85 g, 5.6 mmol)and 2-(3-fluorophenyl)ethylamine (0.35 g, 2.5 mmol) in acetonitrile (50mL) were refluxed for 10 hours. The mixture was cooled, concentrated,diluted with ethyl acetate, washed twice with aqueous ammonium chlorideand concentrated to dryness. The solid obtained was suspended in ethylacetate and filtered to obtain 0.45 g (65%) of the title compound as atan solid.

Example 1F1-(4-Chloro-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 4-chlorobenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 332 (M+H)⁺; (ESI−) m/z 330 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.62(s, 3H), 4.31 (d, J 4.7, 2H), 7.25 (m, 2H), 7.37 (m, 4H), 8.01 (d, J6.4, 1H), 8.64 (d, J 6.4, 1H), 8.91 (s, 1H), 9.62 (s, 1H); Anal. Calcdfor C₁₆H₁₄ClN₃OS.1.25HCl: C, 50.92; H, 4.07. Found: C, 51.05; H, 3.93.

Example 21-(2,4-Dichloro-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 2,4-dichlorobenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 366 (M+H)⁺; (ESI−) m/z 364 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.45(s, 3H), 4.31 (d, J 6.0, 2H), 7.46 (m, 2H), 7.57 (m, 1H), 7.63 (m, 1H),7.86 (d, J 6.4, 1H), 8.58 (d, J 6.4, 1H), 8.73 (s, 1H), 9.47 (s, 1H);Anal. Calcd for C₁₆H₁₃Cl₂N₃OS.1.1HCl: C, 47.29; H, 3.50; N, 10.34.Found: C, 47.61; H, 3.15; N, 10.20.

Example 31-(3,4-Dichloro-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 3,4-dichlorobenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 366 (M+H)⁺; (ESI−) m/z 364 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.44(s, 3H), 4.28 (d, J 6.1, 2H), 6.91 (t, J 6.1, 1H), 7.30 (d, J 8.2, 1H),7.44 (d, J 5.2, 1H), 7.54 (s, 1H), 7.60 (d, J 8.2, 1H), 8.26 (s, 1H),8.41 (d, J 5.2, 1H), 9.07 (s, 1H); Anal. Calcd for C₁₆H₁₃Cl₂N₃OS.1.1HCl:C, 47.29; H, 3.50; N, 10.34. Found: C, 47.48; H, 3.25; N, 10.16.

Example 41-(2-Methyl-thieno[2,3-c]pyridin-3-yl)-3-[1-methyl-1-(4-trifluoromethyl-phenyl)-ethyl]-urea

The title compound was prepared using1-methyl-1-(4-trifluoromethyl-phenyl)-ethylamine, the product fromExample 1A, DBU and the procedure described in Example 1B. MS (ESI+) m/z394 (M+H)⁺; (ESI−) m/z 392 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 1.63 (s, 6H), 2.53(s, 3H), 7.08 (s, 1H), 7.66 (m, 2H), 7.75 (d, J 6.1, 1H), 8.29 (s, 1H),8.56 (d, J 6.1, 1H), 9.42 (s, 1H); Anal. Calcd forC₁₆H₁₃Cl₂N₃OS.1CF₃CO₂H.0.5H₂O: C, 48.84; H, 3.90; N, 8.14. Found: C,49.08; H, 3.76; N, 7.98.

Example 51-(2,3-Difluoro-4-trifluoromethyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using2,3-difluoro-4-trifluoromethylbenzylamine, the product from Example 1A,DBU and the procedure described in Example 1B. MS (ESI+) m/z 402 (M+H)⁺;(ESI−) m/z 400 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.62 (s, 3H), 4.48 (d, J 5.4,2H), 7.41 (m, 2H), 7.66 (m, 1H), 8.01 (d, J 6.4, 1H), 8.65 (d, J 6.4,1H), 9.07 (s, 1H), 9.62 (s, 1H); Anal. Calcd for C₁₇H₁₂F₅N₃OS.1.2HCl: C,45.87; H, 2.99; N, 9.44. Found: C, 45.84; H, 2.84; N, 9.29.

Example 61-(2,4-Bis-trifluoromethyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using2,4-di(trifluoromethyl)benzylamine, the product from Example 1A, DBU andthe procedure described in Example 1B.

MS (ESI+) m/z 434 (M+H)⁺; (ESI−) m/z 432 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.68(s, 3H), 4.67 (d, J 5.8, 2H), 7.17 (t, J 6.1, 1H), 7.84 (m, 2H), 8.01(s, 1H), 8.15 (d, J 7.8, 1H), 8.58 (d, J 6.1, 1H), 8.65 (s, 1H), 9.44(s, 1H); Anal. Calcd for C₁₈H₁₃F₆N₃OS.0.85CF₃CO₂H: C, 44.62; H, 2.63; N,7.92. Found: C, 44.92; H, 2.63; N, 7.56.

Example 71-(2-Chloro-4-trifluoromethyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using2-chloro-4-trifluoromethylbenzylamine, the product from Example 1A, DBUand the procedure described in Example 1B.

MS (ESI+) m/z 400 (M+H)⁺; (ESI−) m/z 398 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.63(s, 3H), 4.45 (d, J 5.8, 2H), 7.30 (t, J 6.1, 1H), 7.64 (d, J 8.1, 1H),7.80 (m, 2H), 7.86 (s, 1H), 7.99 (d, J 6.4, 1H), 8.64 (d, J 6.4, 1H),8.95 (s, 1H), 9.59 (s, 1H); Anal. Calcd for C₁₇H₁₃ClF₃N₃OS.0.6CF₃CO₂H:C, 46.69; H, 2.93; N, 8.97. Found: C, 46.64; H, 3.15; N, 9.02.

Example 81-(4-Bromo-3-methyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 4-bromo-3-methylbenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.

MS (ESI+) m/z 366 (M+H)⁺; (ESI−) m/z 364 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.34(s, 3H), 2.55 (s, 3H), 4.24 (d, J 5.8, 2H), 6.93 (t, J 6.1, 1H), 7.07(m, 1H), 7.27 (s, 1H), 7.54 (d, J 8.1, 1H), 7.77 (d, J 6.1, 1H), 8.37(s, 1H), 8.56 (d, J 6.1, 1H), 9.41 (s, 1H); Anal. Calcd forC₁₇H₁₆BrN₃OS.CF₃CO₂H: C, 45.25; H, 3.40; N, 8.33. Found: C, 45.22; H,3.46; N, 8.35.

Example 91-(4-trifluoromethoxy-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 4-trifluoromethoxybenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.

¹H NMR (DMSO-d₆) δ 2.44 (s, 3H), 4.31 (d, J 4.7, 2H), 6.86 (t, J 6.0,1H), 7.33 (d, J 7.9, 2H), 7.43 (m, 3H), 8.17 (s, 1H), 8.40 (d, J 5.5,1H), 9.05 (s, 1H).

Example 101-(3-trifluoromethylbenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 3-trifluoromethylbenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.

¹H NMR (DMSO-d₆) δ 2.44 (s, 3H), 4.37 (d, J 4.7, 2H), 6.94 (t, J 6.0,1H), 7.42 (d, J 7.9, 1H), 7.59 (m, 4H), 8.24 (s, 1H), 8.39 (d, J 5.5,1H), 9.05 (s, 1H).

Example 111-(3-Trifluoromethoxybenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 3-trifluoromethoxybenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.

¹H NMR (DMSO-d₆) δ 2.43 (s, 3H), 4.32 (d, J 5.9, 2H), 6.99 (t, J 6.0,1H), 7.22 (d, J 7.2, 1H), 7.26 (s, 1H), 7.32 (d, J 8.0, 1H), 7.45 (m,2H), 8.19 (s, 1H), 8.39 (d, J 5.5, 1H), 9.05 (s, 1H).

Example 12 (2-Methyl-thieno[2,3-c]pyridin-3-yl)-carbamic acid4-trifluoromethyl-benzyl ester

The title compound was prepared using 4-trifluoromethoxybenzyl alcohol,the product from Example 1A, DBU and the procedure described in Example1B. ¹H NMR (DMSO-d₆) δ 2.45 (s, 3H), 5.27 (d, J 4.7, 2H), 6.86 (t, J6.0, 1H), 7.33 (d, J 7.9, 2H), 7.43 (m, 3H), 8.17 (s, 1H), 8.40 (d, J5.5, 1H), 9.05 (s, 1H).

Example 13 (2-Methyl-thieno[2,3-c]pyridin-3-yl)-carbamic acid4-trifluoromethoxy-benzyl ester

The title compound was prepared using 4-trifluoromethoxybenzyl alcohol,the product from Example 1A, DBU and the procedure described in Example1B. ¹H NMR (DMSO-d₆) δ 2.44 (s, 3H), 5.19 (s, 2H), 6.86 (t, J 6.0, 1H),7.42 (m, 3H), 7.57 (m, 2H), 8.40 (d, J 5.5, 1H), 9.08 (s, 1H), 9.45 (s,1H).

Example 14 (2-Methyl-thieno[2,3-c]pyridin-3-yl)-carbamic acid4-trifluoromethylsulfanyl-benzyl ester

The title compound was prepared using4-trifluoromethylsulfanyl-benzyl_alcohol, the product from Example 1A,DBU and the procedure described in Example 1B.

¹H NMR (DMSO-d₆) δ 2.45 (s, 3H), 5.24 (s, 2H), 7.46 (d, J 5.5, 1H), 7.61(m, 2H), 7.76 (m, 2H), 8.40 (d, J 5.5, 1H), 9.08 (s, 1H), 9.50 (s, 1H).

Example 15 1-Benzyl-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using benzylamine, the product fromExample 1A, DBU and the procedure described in Example 1B. MS (ESI+) m/z298 (M+H)⁺; (ESI−) m/z 396 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.57 (s, 3H), 4.31(d, J 4.7, 2H), 7.03 (t, J 6.0, 1H), 7.26 (m, 1H), 7.33 (m, 5H), 7.84(d, J 6.2, 1H), 8.48 (s, 1H), 8.58 (d, J 5.5, 1H), 9.48 (s, 1H).

Example 161-(2-Methyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 2-methylbenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 312 (M+H)⁺; (ESI−) m/z 310 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.30(s, 3H), 2.57 (s, 3H), 4.30 (d, J 4.7, 2H), 6.87 (t, J 6.0, 1H), 7.18(m, 3H), 7.29 (d, 1H), 7.83 (d, J 6.2, 1H), 8.39 (s, 1H), 8.58 (d, J5.5, 1H), 9.46 (s, 1H).

Example 171-(3-Methyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 3-methylbenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 312 (M+H)⁺; (ESI−) m/z 310 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.31(s, 3H), 2.57 (s, 3H), 4.28 (d, J 4.7, 2H), 6.95 (t, J 6.0, 1H), 7.15(m, 3H), 7.24 (m, 1H), 7.81 (d, J 6.2, 1H), 8.41 (s, 1H), 8.58 (d, J5.5, 1H), 9.45 (s, 1H).

Example 181-(4-Methyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 4-methylbenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 312 (M+H)⁺; (ESI−) m/z 310 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.29(s, 3H), 2.56 (s, 3H), 4.26 (d, J 4.7, 2H), 6.94 (t, J 6.0, 1H), 7.15(d, 2H), 7.20 (d, 2H), 7.81 (d, J 6.2, 1H), 8.41 (s, 1H), 8.58 (d, J5.5, 1H), 9.45 (s, 1H).

Example 191-(3-Fluoro-5-trifluoromethyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using3-fluoro-5-trifluoromethyl-benzylamine, the product from Example 1A, DBUand the procedure described in Example 1B.

MS (ESI+) m/z 384 (M+H)⁺; (ESI−) m/z 382 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.55(s, 3H), 4.40 (d, J 4.7, 2H), 7.12 (t, J 6.0, 1H), 7.45 (d, 1H), 7.54(s, 1H), 7.78 (d, J 6.2, 1H), 8.53 (s, 1H), 8.57 (d, J 5.5, 1H), 9.43(s, 1H).

Example 201-(4-Methoxy-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 4-methoxybenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 328

(M+H)⁺; (ESI−) m/z 326 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.29 (s, 3H), 2.56 (s,3H), 4.26 (d, J 4.7, 2H), 6.94 (t, J 6.0, 1H), 7.15 (d, 2H), 7.20 (d,2H), 7.81 (d, J 6.2, 1H), 8.41 (s, 1H), 8.58 (d, J 5.5, 1H), 9.45 (s,1H).

Example 211-(2-Fluorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 2-fluorobenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 316 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 2.56 (s, 3H), 4.36 (d, J 4.7,2H), 6.87 (t, J 6.0, 1H), 7.19 (m, 1H), 7.26 (m, 1H), 7.40 (m, 1H), 7.66(m, 1H), 7.80 (d, J 6.2, 1H), 8.41 (s, 1H), 8.56 (d, J 5.5, 1H), 9.44(s, 1H).

Example 221-(3-Fluorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 3-fluorobenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 316 (M+H)⁺; (ESI−) m/z 314 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.57(s, 3H), 4.33 (d, J 4.7, 2H), 7.05-7.18 (m, 4H), 7.38 (m, 1H), 7.84 (d,J 6.2, 1H), 8.53 (s, 1H), 8.59 (d, J 5.5, 1H), 9.48 (s, 1H).

Example 231-(4-Fluorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 4-fluorobenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 316 (M+H)⁺; (ESI−) m/z 314 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.56(s, 3H), 4.29 (d, J 4.7, 2H), 7.04 (t, J 6.0, 1H), 7.17 (m, 2H), 7.36(m, 2H), 7.83 (d, J 6.2, 1H), 8.49 (s, 1H), 8.59 (d, J 5.5, 1H), 9.48(s, 1H).

Example 241-(2-Chlorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 2-chlorobenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 332 (M+H)⁺; (ESI−) m/z 330 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.58(s, 3H), 4.39 (d, J 4.7, 2H), 7.05 (t, J 6.0, 1H), 7.31 (d, J 6.2, 1H),7.37 (d, J 6.2, 1H), 7.44 (m, 2H), 7.83 (d, J 6.2, 1H), 8.57 (s, 1H),8.58 (d, J 5.5, 1H), 9.46 (s, 1H).

Example 251-(3-Chlorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 3-chlorobenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 332 (M+H)⁺; (ESI−) m/z 330 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.56(s, 3H), 4.33 (d, J 4.7, 2H), 7.03 (t, J 6.0, 1H), 7.29 (m, 2H), 7.37(m, 1H), 7.49 (m, 1H), 7.80 (d, J 6.2, 1H), 8.45 (s, 1H), 8.57 (d, J5.5, 1H), 9.44 (s, 1H).

Example 26 1-(2-Bromobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 2-bromobenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 378 (M+H)⁺; (ESI−) m/z 376 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.58(s, 3H), 4.35 (d, J 4.7, 2H), 7.08 (t, J 5.6, 1H), 7.23 (m, 1H), 7.42(d, J 4.1, 1H), 7.62 (d, J 7.8, 1H), 7.83 (d, J 6.0, 1H), 8.58 (d, J5.9, 1H), 8.62 (s, 1H), 9.46 (s, 1H).

Example 27 1-(3-Bromobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 3-bromobenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 378 (M+H)⁺; (ESI−) m/z 376 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.56(s, 3H), 4.30 (d, J 4.7, 2H), 7.01 (t, J 5.6, 1H), 7.32 (d, J 5.3, 1H),7.45 (m, 1H), 7.51 (s, 1H), 7.80 (d, J 6.0, 1H), 8.43 (s, 1H), 8.58 (d,J 5.9, 1H), 9.44 (s, 1H).

Example 2811-(2-Methyl-thieno[2,3-c]pyridin-3yl)-3-naphthalen-1-ylmethylurea

The title compound was prepared using naphthalene-1-yl-methylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.

MS (ESI+) m/z 348 (M+H)⁺; (ESI−) m/z 346 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.57(s, 3H), 4.79 (d, J 5.6, 2H), 7.01 (t, J 5.6, 1H), 7.32 (m, 5H), 7.83(d, J 6.0, 1H), 7.89 (m, 1H), 7.97 (d, J 7.5, 1H), 8.37 (s, 1H), 8.58(d, J 5.9, 1H), 9.46 (s, 1H).

Example 291-(2,3-Dimethylbenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 2,3-dimethylbenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 326 (M+H)⁺; (ESI−) m/z 324 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.19(s, 3H), 2.26 (s, 3H), 2.54 (s, 3H), 4.30 (d, J 4.7, 2H), 6.72 (t, J6.0, 1H), 7.08 (m, 2H), 7.14 (m, 1H), 7.74 (d, J 5.9, 1H), 8.22 (s, 1H),8.54 (d, J 5.5, 1H), 9.38 (s, 1H).

Example 301-(2,5-Dimethylbenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 2,5-dimethylbenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 326 (M+H)⁺; (ESI−) m/z 324 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.24(s, 3H), 2.27 (s, 3H), 2.56 (s, 3H), 4.25 (d, J 4.7, 2H), 6.76 (t, J6.0, 1H), 6.97 (m, 1H), 7.15 (m, 2H), 7.77 (d, J 5.7, 1H), 8.27 (s, 1H),8.56 (d, J 6.0, 1H), 9.40 (s, 1H).

Example 311-(3,4-Dimethylbenzyl-1)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea

The title compound was prepared using 3,4-dimethylbenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 326 (M+H)⁺; (ESI−) m/z 324 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 2.20(s, 3H), 2.22 (s, 3H), 2.55 (s, 3H), 4.23 (d, J 5.9, 2H), 6.76 (t, J5.9, 1H), 7.02 (m, 1H), 7.09 (m, 2H), 7.77 (d, J 6.2, 1H), 8.31 (s, 1H),8.56 (d, J 5.9, 1H), 9.41 (s, 1H).

Example 321-(2-Methyl-thieno[2,3-c]pyridin-3-yl)-3-(5-piperidin-1-yl-indan-1-yl)-urea

The title compound was prepared using 5-piperidin-1-yl-indan-1-ylamine,the product from Example 1A, DBU and the procedure described in Example1B.

MS (ESI+) m/z 407 (M+H)⁺; (ESI−) m/z 405 (M−H)⁺; ¹H NMR (DMSO-d₆) δ 1.55(m, 7H), 1.73 (m, 1H), 2.50 (s, 3H), 2.73 (m, 1H), 2.85 (m, 1H), 3.09(m, 4H), 5.08 (d, J 7.4, 1H), 6.53 (d, J 8.1, 1H), 6.80 (m, 2H), 7.14(d, J 8.8, 1H), 7.49 (d, J 5.4, 1H), 7.92 (s, 1H), 8.43 (d, J 5.4, 1H),9.06 (s, 1H).

(5) Determination of Biological Activity

(a) In Vitro Data—Determination of Inhibition Potencies

Dulbecco's modified Eagle medium (D-MEM) (with 4.5 mg/mL glucose) andfetal bovine serum were obtained from Hyclone Laboratories, Inc. (Logan,Utah). Dulbecco's phosphate-buffered saline (D-PBS) (with 1 mg/mLglucose and 3.6 mg/l Na pyruvate) (without phenol red), L-glutamine,hygromycin B, and Lipofectamine™ were obtained from Life Technologies(Grand Island, N.Y.). G418 sulfate was obtained fromCalbiochem-Novabiochem Corp. (San Diego, Calif.). Capsaicin(8-methyl-N-vanillyl-6-nonenamide) was obtained from Sigma-Aldrich, Co.(St. Louis, Mo.). Fluo-4 AM(N-[4-[6-[(acetyloxy)methoxy]-2,7-difluoro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-glycine,(acetyloxy)methyl ester) was purchased from Molecular Probes (Eugene,Oreg.).

The cDNAs for the human VR1 receptor were isolated by reversetranscriptase-polymerase chain reaction (RT-PCR) from human smallintestine poly A+RNA supplied by Clontech (Palo Alto, Calif.) usingprimers designed surrounding the initiation and termination codonsidentical to the published sequences (Hayes et al. Pain Vol 88, pages205-215, 2000). The resulting cDNA PCR products were subcloned intopCIneo mammalian expression vector (Promega) and fully sequenced usingfluorescent dye-terminator reagents (Prism, Perkin-Elmer AppliedBiosystems Division) and a Perkin-Elmer Applied Biosystems Model 373 DNAsequencer or Model 310 genetic analyzer. Expression plasmids encodingthe hVR1 cDNA were transfected individually into 1321N1 humanastrocytoma cells using Lipofectamine™. Forty-eight hours aftertransfection, the neomycin-resistant cells were selected with growthmedium containing 800 μg/mL Geneticin (Gibco BRL). Surviving individualcolonies were isolated and screened for VR1 receptor activity. Cellsexpressing recombinant homomeric VR1 receptors were maintained at 37° C.in D-MEM containing 4 mM L-glutamine, 300 μg/mL G418 (Cal-biochem) and10% fetal bovine serum under a humidified 5% CO₂ atmosphere.

The functional activity of compounds at the VR1 receptor was determinedwith a Ca²⁺ influx assay and measurement of intracellular Ca²⁺ levels([Ca²⁺]i). All compounds were tested over an 11-point half-logconcentration range. Compound solutions were prepared in D-PBS (4× finalconcentration), and diluted serially across 96-well v-bottom tissueculture plates using a Biomek 2000 robotic automation workstation(Beckman-Coulter, Inc., Fullerton, Calif.). A 0.2 μM solution of the VR1agonist capsaicin was also prepared in D-PBS. The fluorescent Ca²⁺chelating dye fluo-4 was used as an indicator of the relative levels of[Ca²⁺]i in a 96-well format using a Fluorescence Imaging Plate Reader(FLIPR)(Molecular Devices, Sunnyvale, Calif.). Cells were grown toconfluence in 96-well black-walled tissue culture plates. Then, prior tothe assay, the cells were loaded with 100 μL per well of fluo-4 AM (2μM, in D-PBS) for 1-2 hours at 23° C. Washing of the cells was performedto remove extracellular fluo-4 AM (2×1 mL D-PBS per well), andafterward, the cells were placed in the reading chamber of the FLIPRinstrument. 50 μL of the compound solutions were added to the cells atthe 10th second time mark of the experimental run. Then, after a3-minute time delay, 50 μL of the capsaicin solution was added at the190-second time mark (0.05 μM final concentration) (final volume=200 μL)to challenge the VR1 receptor. Time length of the experimental run was240 seconds. Fluorescence readings were made at 1 to 5 second intervalsover the course of the experimental run. The peak increase in relativefluorescence units (minus baseline) was calculated from the 190th secondtime mark to the end of the experimental run, and expressed as apercentage of the 0.05 μM capsaicin (control) response. Curve-fits ofthe data were solved using a four-parameter logistic Hill equation inGraphPad Prism® (GraphPad Software, Inc., San Diego, Calif.), and IC₅₀values were calculated.

The compounds of the present invention were found to be antagonists ofthe vanilloid receptor subtype 1 (VR1) receptor with IC_(50s) from 5000nM to 0.1 nM. In a preferred range, twelve (12) compounds tested hadIC_(50s) from 500 nM to 0.1 nM. In a more preferred range, six (6)compounds tested had IC_(50s) from 100 nM to 0.1 nM.

(b) In Vivo Data—Determination of Antinociceptive Effect

Experiments were performed on 400 adult male 129 J mice (Jacksonlaboratories, Bar Harbor, Me.), weighing 20-25 g. Mice were kept in avivarium, maintained at 22° C., with a 12 hour alternating light-darkcycle with food and water available ad libitum. All experiments wereperformed during the light cycle. Animals were randomly divided intoseparate groups of 10 mice each. Each animal was used in one experimentonly and was sacrificed immediately following the completion of theexperiment. All animal handling and experimental procedures wereapproved by an IACUC Committee.

The antinociceptive test used was a modification of the abdominalconstriction assay described in Collier, et al., Br. J. Pharmacol.Chemother. Vol. 32 pages 295-310 (1968). Each animal received anintraperitoneal (i.p.) injection of 0.3 mL of 0.6% acetic acid in normalsaline to evoke writhing. Animals were placed separately under clearcylinders for the observation and quantification of abdominalconstriction. Abdominal constriction was defined as a mild constrictionand elongation passing causally along the abdominal wall, accompanied bya slight twisting of the trunk and followed by bilateral extension ofthe hind limbs. The total number of abdominal constrictions was recordedfrom 5 to 20 minutes after acetic acid injection. The ED_(50s) weredetermined based on the i.p. injection.

The other antinociceptive test used was Complete Freund'sAdjuvant-induced Thermal Hyperalgesia (CFA) assay described in Pircio etal. Eur J. Pharmacol. Vol. 31 (2) pages 207-215 (1975). Chronicinflammatory hyperalgesia was induced in one group of rats following theinjection of complete Freund's adjuvant (CFA, 50%, 150 μL) into theplantar surface of the right hindpaw 48 hours prior to testing. Thermalnociceptive thresholds were measured in three different groups of rats.The ED_(50s) were determined based on the oral administration. The ED₅₀values for two compounds tested were 30 and 10 mmol/kg.

The in vitro and in vivo data demonstrates that compounds of the presentinvention antagonize the VR1 receptor and are useful for treating pain.

Compounds of the present invention, as VR1 antagonists, are also usefulfor ameliorating or preventing additional disorders that are affected bythe VR1 receptors such as, but not limited to, inflammatory thermalhyperalgesia, bladder overactivity, and urinary incontinence.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used to treat pain as demonstrated byNolano, M. et al., Pain Vol. 81 pages 135-145 (1999); Caterina, M. J.and Julius, D., Annu. Rev. Neurosci. Vol. 24, pages 487-517 (2001);Caterina, M. J. et al., Science Vol. 288 pages 306-313 (2000); Caterina,M. J. et al., Nature Vol. 389, pages 816-824 (1997).

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used to treat bladder overactivityand/or urinary incontinence as demonstrated by Fowler, C. Urology Vol.55 pages 60-64 (2000).

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used to treat inflammatory thermalhyperalgesia as demonstrated by Davis, J. et al., Nature Vol. 405 pages183-187 (2000).

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention. The pharmaceuticalcompositions comprise compounds of the present invention formulatedtogether with one or more non-toxic pharmaceutically acceptablecarriers. The pharmaceutical compositions can be specially formulatedfor oral administration in solid or liquid form, for parenteralinjection or for rectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions that are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals, which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), Poste et al., Chapter 4, p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants that may berequired. Ophthalmic formulations, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s), which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. The phrase “therapeutically effectiveamount” of the compound of the invention means a sufficient amount ofthe compound to treat disorders, at a reasonable benefit/risk ratioapplicable to any medical treatment. It will be understood, however,that the total daily usage of the compounds and compositions of thepresent invention will be decided by the attending physician within thescope of sound medical judgement. The specific therapeutically effectivedose level for any particular patient will depend upon a variety offactors including the disorder being treated and the severity of thedisorder; activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well-known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences Vol. 66, pages 1 et seq (1977).The salts can be prepared in situ during the final isolation andpurification of the compounds of the invention or separately by reactinga free base function with a suitable organic acid. Representative acidaddition salts include, but are not limited to acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as, but not limited to, methyl, ethyl, propyl,and butyl chlorides, bromides and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides suchas, but not limited to, decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; arylalkyl halides like benzyl and phenethylbromides and others. Water or oil-soluble or dispersible products arethereby obtained. Examples of acids which can be employed to formpharmaceutically acceptable acid addition salts include such inorganicacids as hydrochloric acid, hydrobromic acid, sulfuric acid, andphosphoric acid and such organic acids as acetic acid, fumaric acid,maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citricacid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use. Prodrugs of the present invention may be rapidlytransformed in vivo to compounds of formula (I), for example, byhydrolysis in blood.

The present invention contemplates compounds of formula I formed bysynthetic means or formed by in vivo biotransformation.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.01 to about 100mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.1 to about 25 mg/kg/day. If desired,the effective daily dose can be divided into multiple doses for purposesof administration; consequently, single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose.

Compounds of the present invention were named by ACD/ChemSketch version5.0 (developed by Advanced Chemistry Development, Inc., Toronto, ON,Canada) or were given names, which appeared to be consistent with ACDnomenclature.

Abbreviations

Abbreviations which have been used in the descriptions of the Schemesand the Examples that follow are: DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC for 1,3-dicyclohexylcarbodiimide; DMAP for4-dimethylaminopyridine; DMF for N,N-dimethylformamide; DMSO fordimethylsulfoxide; EDCI or EDC for1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride; HPLChigh pressure liquid chromatography; NBS for N-bromosuccinimide; psi forpounds per square inch; and THF for tetrahydrofuran.

We claim:
 1. A method of treating a disorder selected from the groupconsisting of pain, urinary incontinence, and bladder overactivity in ahost mammal in need of such treatment comprising administering to thehost mammal a therapeutically effective amount of a compound of formula(I):

or a pharmaceutically acceptable salt thereof, wherein - - - is absentor a covalent bond; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ is CR₄; X₅ isselected from N and CH₂; X₆ is selected from O, NH and S; Z₁ is selectedfrom O, NH and S; Z₂ is absent or selected from NH and O; L is selectedfrom aryl, alkenylene, alkylene, alkynylene, cycloalkylene, heterocycle,—(CH₂)_(m)O(CH₂)_(n)—, —N(H)O—, and —NHNH— wherein the left end of—(CH₂)_(m)O(CH₂)_(n)— and —N(H)O— is attached to Z₂ and the right end isattached to R₇; provided that when Z₂ is NH or O then L is other than—N(H)O— or —NHNH—; m and n are each independently 1-6; R₁, R₃ and R₅ areeach independently selected from hydrogen, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl,amines, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl,cycloalkylalkyl, ethylenedioxy, formyl, formylalkyl, haloalkoxy,haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl,methylenedioxy, mercapto, mercaptoalkyl, nitro, (CF₃)₂(HO)C—,R_(B)S(O)₂R_(A)N—, R_(A)OS(O)₂—, R_(B)—S(O)₂—, Z_(A)Z_(B)N—,(Z_(A)Z_(B)N)alkyl, (Z_(A)Z_(B)N)carbonyl, (Z_(A)Z_(B)N)alkylcarbonyland (Z_(A)Z_(B)N)sulfonyl, wherein Z_(A) and Z_(B) are eachindependently selected from hydrogen, alkyl, alkylcarbonyl, formyl, aryland arylalkyl; R₂ and R₄ are each independently selected from the groupconsisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, amines,carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl,ethylenedioxy, formyl, formylalkyl, haloalkoxy, haloalkyl,haloalkylthio, halogen, hydroxy, hydroxyalkyl, methylenedioxy, mercapto,mercaptoalkyl, nitro, (CF₃)₂(HO)C—, R_(B)S(O)₂R_(A)N—, R_(A)OS(O)₂—,R_(B)—S(O)₂—, Z_(A)Z_(B)N—, (Z_(A)Z_(B)N)alkyl, (Z_(A)Z_(B)N)carbonyl,(Z_(A)Z_(B)N)alkylcarbonyl, (ZAZ_(B)N)sulfonyl, (Z_(A)Z_(B)N)C(═NH)—,(Z_(A)Z_(B)N)C(═NCN)NH—, and (Z_(A)Z_(B)N)C(═NH)NH—; R_(A) is selectedfrom hydrogen and alkyl; R_(B) is selected from alkyl, aryl andarylalkyl; R₆ is absent or selected from hydrogen and alkyl; providedthat R₆ is absent when X₅ is CH₂ and R₆ is selected from hydrogen andalkyl when X₅ is N; and R₇ is selected from hydrogen, aryl andheterocycle.
 2. The method of claim 1 wherein the disorder is pain. 3.The method of claim 1 wherein the disorder is urinary incontinence. 4.The method of claim 1 wherein the disorder is bladder overactivity. 5.The method of claim 1 wherein the compound of formula (I) is selectedfrom the group consisting of:1-(4-chloro-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(2,4-dichloro-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(3,4-dichloro-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(2-methyl-thieno[2,3-c]pyridin-3-yl)-3-[1-methyl-1-(4-trifluoromethylphenyl)-ethyl]-urea;1-(2,3-difluoro-4-trifluoromethyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(2,4-bis-trifluoromethyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(2-chloro-4-trifluoromethyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(4-bromo-3-methyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(4-trifluoromethoxy-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(3-trifluoromethylbenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(3-trifluoromethoxybenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;(2-methyl-thieno[2,3-c]pyridin-3-yl)-carbamic acid4-trifluoromethyl-benzyl ester;(2-methyl-thieno[2,3-c]pyridin-3-yl)-carbamic acid4-trifluoromethoxy-benzyl ester;(2-methyl-thieno[2,3-c]pyridin-3-yl)-carbamic acid4-trifluoromethylsulfanyl-benzyl ester;1-benzyl-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(2-methyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(3-methyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(4-methyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(3-Fluoro-5-trifluoromethyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(4-methoxy-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(2-fluorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(3-fluorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(4-fluorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(2-chlorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(3-chlorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(2-bromobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(3-bromobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(2-methyl-thieno[2,3-c]pyridin-3-yl)-3-naphthalen-1-ylmethylurea;1-(2,3-dimethylbenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(2,5-dimethylbenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea;1-(3,4-dimethylbenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea; and1-(2-methyl-thieno[2,3-c]pyridin-3-yl)-3-(5-piperidin-1-yl-indan-1-yl)-urea.